Abstract
Duchenne muscular dystrophy (DMD) is a common X-linked recessive disease of muscle degeneration and death. In order to provide accurate and reliable genetic counseling and prenatal diagnosis, we screened DMD mutations in a cohort of 119 Chinese patients using multiplex ligation-dependent probe amplification (MLPA) and denaturing high performance liquid chromatography (DHPLC) followed by Sanger sequencing. In these unrelated DMD patients, we identified 11 patients with DMD small mutations (9.2%) and 81 patients with DMD deletions/duplications (del/dup) (68.1%), of which 64 (79.0%) were deletions, 16 (19.8%) were duplications, and one (1.2%) was both deletion and duplication. Furthermore, we analyzed the frequency of DMD breakpoint in the 64 deletion cases by calculating exon-deletion events of certain exon interval that revealed a novel mutation hotspot boundary. To explore why DMD rearrangement breakpoints were predisposed to specific regions (hotspot), we precisely characterized junction sequences of breakpoints at the nucleotide level in 21 patients with exon deleted/duplicated in DMD with a high-resolution SNP microarray assay. There were no exactly recurrent breakpoints and there was also no significant difference between single-exon del/dup and multiple-exon del/dup cases. The data from the current study provided a comprehensive strategy to detect DMD mutations for clinical practice, and identified two deletion hotspots at exon 43–55 and exon 10–23 by calculating exon-deletion events of certain exon interval. Furthermore, this is the first study to characterize DMD breakpoint at the nucleotide level in a Chinese population. Our observations provide better understanding of the mechanism for DMD gene rearrangements.
Highlights
Duchenne muscular dystrophy (DMD; OMIM #310200) is an X-linked recessive disease that affects approximately 1 in 3500 male living births and results in muscle degeneration and death [1,2]
DMD deletions and duplications are major alterations of DMD patients; we analyzed 119 unrelated DMD Chinese patients using multiplex ligation-dependent probe amplification (MLPA) and found that among them, a gross mutation was detected in 81 patients (68.1%)
The distances between two adjacent exons are different across the DMD gene; the increased numbers of exon del/dup events could be caused by extended exon interval length
Summary
Duchenne muscular dystrophy (DMD; OMIM #310200) is an X-linked recessive disease that affects approximately 1 in 3500 male living births and results in muscle degeneration and death [1,2]. Alteration or loss of dystrophin forces excess calcium into the cell membrane, resulting in excess water in the mitochondria; the affected skeletal muscle will undergo dystrophy, mitochondrial dysfunction, and necrosis. Approximately 70% of DMD cases are caused by deletions/ duplications (del/dup) of one or more DMD exons and 30% of cases have DMD mutations of nucleotide level. Deletions/ duplications are the most common type of disease-causing mutation of the DMD gene. Deletion hotspots reside in both the distal and proximal region of the DMD gene, while duplications more frequently involve the DMD 59 region [5]. It is essential to make a prenatal diagnosis and provide genetic counseling to reduce birth of such boys
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